Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 282405, 9 pages http://dx.doi.org/10.1155/2015/282405
Review Article Ocular Manifestations and Therapeutic Options in Patients with Familial Amyloid Polyneuropathy: A Systematic Review A. C. Martins,1 A. M. Rosa,1,2 E. Costa,1,2 C. Tavares,1,2 M. J. Quadrado,1,2 and J. N. Murta1,2 1
Centro Hospitalar e Universit´ario de Coimbra, Avenida Bissaya Barreto-Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
2
Correspondence should be addressed to A. M. Rosa; [email protected] Received 22 May 2015; Accepted 27 July 2015 Academic Editor: Mar´ıa D. Pinazo-Dur´an Copyright © 2015 A. C. Martins et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. This paper aims to review the morphological and functional characteristics of patients affected by familial amyloid polyneuropathy (FAP), with greater focus on type I and its progression after liver transplantation. We also analyse therapeutic options for the ophthalmic manifestations. Methods. The literature from 2002 through 2015 was reviewed, with a total of 45 articles studied, using the key terms related to amyloidosis and its therapeutic approaches. Information was collated, evaluated, critically assessed, and then summarised in its present form. Pathophysiology and Treatment. FAP results from mutation of the transthyretin gene, with Val30Met being the most frequent substitution. The symptoms are those typical of a sensorimotor autonomic neuropathy and can be halted with liver transplantation. Nowadays there are new medical therapies that delay the progression of the systemic neuropathy. However, there are still no options to avoid ocular disease. Conclusion. The main ocular manifestations in patients with FAP type I are amyloid deposition in the vitreous, dry eye, and secondary glaucoma. Despite liver transplantation, eye synthesis of amyloid persists and is associated with progressive ocular manifestations, which require continued ophthalmologic follow-up. New therapeutic strategies are therefore needed, particularly to target the ocular synthesis of the abnormal protein.
1. Introduction Amyloidosis is a group of diseases characterised by deposition of amyloid, consisting of clumps of insoluble proteins at the level of the peripheral or central nervous system [1]. Its phenotype varies depending on the affected organs [2]. This condition may be primary in origin, very often hereditary and leading to familial amyloid polyneuropathy (FAP), or secondary to chronic inflammatory diseases and causing a sporadic form of the disease, senile systemic amyloidosis (SSA) [3, 4]. The latter is age related and has a milder clinical picture, mainly affecting the heart [5, 6]. FAP is a progressive autosomal dominant neurodegenerative disease, characterised by the accumulation of amyloid in the peripheral nerves and other organs, including the eye. It shows high phenotypic and genotypic heterogeneity, with incomplete penetrance and variable age of onset [7, 8]. It can be classified into three main types, according to the amyloid-forming precursor protein. The most common is transthyretin (TTR), and the others are apolipoprotein A-1 (ApoA1 ratio) and gelsolin (AGel) [9].
FAP originates from mutations of the TTR gene [10]. Over 100 different mutations have been described [1, 9]. The substitution of valine for methionine at position 30 of the TTR gene (Val30Met) is the commonest and the most studied mutation worldwide [11]. This mutation is responsible for the high prevalence of the disease in endemic areas, particularly the north of Portugal, Sweden, and Japan [6]. FAP can thus be classified according to its clinical characteristics and geographical origin [4]: (i) Type I/Portuguese Type/ATTR: it is the most common type and primarily affects the lower limbs, with severe autonomic dysfunction. Portugal, Sweden, and Japan are endemic areas. (ii) Type II/ATTR: polyneuropathy starts in the upper limbs, with mild autonomic dysfunction; it is common in families in Switzerland and Germany. (iii) Type III/ApoA1: polyneuropathy, renal failure, and cranial neuropathy are also characteristic.
2
BioMed Research International (iv) Type IV/Type AGel: lattice corneal dystrophy type II is characteristic; it is more common in Finnish, Irish, American, and Japanese families; apart from polyneuropathy it is characterised by cutaneous hyperextensibility.
FAP has also been divided into three stages according to the progression of neuropathy [2]: (i) Stage I: there is impairment of the lower limbs, without difficulty in walking. (ii) Stage II (after 5-6 years): there is impairment of the upper limbs and there is need for aid in walking. (iii) Stage III (after 10 years): there is total dependence.
2. Methods We performed a systematic review of English- and Portuguese-language articles, restricted to studies published from 2002 through 2015, with a total of 45 articles related to ocular manifestations in FAP and the therapeutic options. We used terms such as amyloidosis, transthyretin, familial amyloid polyneuropathy, clinical trial, ocular manifestations, diflunisal, tafamidis, liver transplantation, small interfering RNA, antisense oligonucleotides, pharmaceutical company names, and other related terms, alone and in various combinations, as keywords. Incidence rates and availability of therapeutic approaches and their relative risks were assessed. The materials were collated, evaluated, critically assessed, and then summarised in their present form.
3. Structure and Function of TTR TTR is a protein circulating in the blood at a concentration of 20–40 mg/dL, forming a stable tetramer. It carries retinol and, in a lesser amount, thyroxine (T4) [1]. If not attached to TTR, retinol is filtered by the kidneys and excreted in urine [12]. The TTR gene is located on chromosome 18 (18q12.1) [6, 13]. When mutated, its tetramer conformation turns into monomers that aggregate and form amyloid deposits [1, 2]. TTR is also present in the cerebrospinal fluid and aqueous humour [5]. About 90% [11, 14] is synthesised and secreted by the liver and a small portion (
Review Article Ocular Manifestations and Therapeutic Options in Patients with Familial Amyloid Polyneuropathy: A Systematic Review A. C. Martins,1 A. M. Rosa,1,2 E. Costa,1,2 C. Tavares,1,2 M. J. Quadrado,1,2 and J. N. Murta1,2 1
Centro Hospitalar e Universit´ario de Coimbra, Avenida Bissaya Barreto-Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
2
Correspondence should be addressed to A. M. Rosa; [email protected] Received 22 May 2015; Accepted 27 July 2015 Academic Editor: Mar´ıa D. Pinazo-Dur´an Copyright © 2015 A. C. Martins et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. This paper aims to review the morphological and functional characteristics of patients affected by familial amyloid polyneuropathy (FAP), with greater focus on type I and its progression after liver transplantation. We also analyse therapeutic options for the ophthalmic manifestations. Methods. The literature from 2002 through 2015 was reviewed, with a total of 45 articles studied, using the key terms related to amyloidosis and its therapeutic approaches. Information was collated, evaluated, critically assessed, and then summarised in its present form. Pathophysiology and Treatment. FAP results from mutation of the transthyretin gene, with Val30Met being the most frequent substitution. The symptoms are those typical of a sensorimotor autonomic neuropathy and can be halted with liver transplantation. Nowadays there are new medical therapies that delay the progression of the systemic neuropathy. However, there are still no options to avoid ocular disease. Conclusion. The main ocular manifestations in patients with FAP type I are amyloid deposition in the vitreous, dry eye, and secondary glaucoma. Despite liver transplantation, eye synthesis of amyloid persists and is associated with progressive ocular manifestations, which require continued ophthalmologic follow-up. New therapeutic strategies are therefore needed, particularly to target the ocular synthesis of the abnormal protein.
1. Introduction Amyloidosis is a group of diseases characterised by deposition of amyloid, consisting of clumps of insoluble proteins at the level of the peripheral or central nervous system [1]. Its phenotype varies depending on the affected organs [2]. This condition may be primary in origin, very often hereditary and leading to familial amyloid polyneuropathy (FAP), or secondary to chronic inflammatory diseases and causing a sporadic form of the disease, senile systemic amyloidosis (SSA) [3, 4]. The latter is age related and has a milder clinical picture, mainly affecting the heart [5, 6]. FAP is a progressive autosomal dominant neurodegenerative disease, characterised by the accumulation of amyloid in the peripheral nerves and other organs, including the eye. It shows high phenotypic and genotypic heterogeneity, with incomplete penetrance and variable age of onset [7, 8]. It can be classified into three main types, according to the amyloid-forming precursor protein. The most common is transthyretin (TTR), and the others are apolipoprotein A-1 (ApoA1 ratio) and gelsolin (AGel) [9].
FAP originates from mutations of the TTR gene [10]. Over 100 different mutations have been described [1, 9]. The substitution of valine for methionine at position 30 of the TTR gene (Val30Met) is the commonest and the most studied mutation worldwide [11]. This mutation is responsible for the high prevalence of the disease in endemic areas, particularly the north of Portugal, Sweden, and Japan [6]. FAP can thus be classified according to its clinical characteristics and geographical origin [4]: (i) Type I/Portuguese Type/ATTR: it is the most common type and primarily affects the lower limbs, with severe autonomic dysfunction. Portugal, Sweden, and Japan are endemic areas. (ii) Type II/ATTR: polyneuropathy starts in the upper limbs, with mild autonomic dysfunction; it is common in families in Switzerland and Germany. (iii) Type III/ApoA1: polyneuropathy, renal failure, and cranial neuropathy are also characteristic.
2
BioMed Research International (iv) Type IV/Type AGel: lattice corneal dystrophy type II is characteristic; it is more common in Finnish, Irish, American, and Japanese families; apart from polyneuropathy it is characterised by cutaneous hyperextensibility.
FAP has also been divided into three stages according to the progression of neuropathy [2]: (i) Stage I: there is impairment of the lower limbs, without difficulty in walking. (ii) Stage II (after 5-6 years): there is impairment of the upper limbs and there is need for aid in walking. (iii) Stage III (after 10 years): there is total dependence.
2. Methods We performed a systematic review of English- and Portuguese-language articles, restricted to studies published from 2002 through 2015, with a total of 45 articles related to ocular manifestations in FAP and the therapeutic options. We used terms such as amyloidosis, transthyretin, familial amyloid polyneuropathy, clinical trial, ocular manifestations, diflunisal, tafamidis, liver transplantation, small interfering RNA, antisense oligonucleotides, pharmaceutical company names, and other related terms, alone and in various combinations, as keywords. Incidence rates and availability of therapeutic approaches and their relative risks were assessed. The materials were collated, evaluated, critically assessed, and then summarised in their present form.
3. Structure and Function of TTR TTR is a protein circulating in the blood at a concentration of 20–40 mg/dL, forming a stable tetramer. It carries retinol and, in a lesser amount, thyroxine (T4) [1]. If not attached to TTR, retinol is filtered by the kidneys and excreted in urine [12]. The TTR gene is located on chromosome 18 (18q12.1) [6, 13]. When mutated, its tetramer conformation turns into monomers that aggregate and form amyloid deposits [1, 2]. TTR is also present in the cerebrospinal fluid and aqueous humour [5]. About 90% [11, 14] is synthesised and secreted by the liver and a small portion (
![[Ocular involvement in familial amyloid polyneuropathy].](/assets/img/hold.png)
